A framework for inferring and analyzing pharmacotherapy treatment patterns.

BACKGROUND: To discover pharmacotherapy prescription patterns and their statistical associations with outcomes through a clinical pathway inference framework applied to real-world data. METHODS: We apply machine learning steps in our framework using a 2006 to 2020 cohort of veterans with major depressive disorder (MDD). Outpatient antidepressant pharmacy fills, dispensed inpatient antidepressant medications, emergency department visits, self-harm, and all-cause mortality data were extracted from the Department of Veterans Affairs Corporate Data Warehouse. RESULTS: Our MDD cohort consisted of 252,179 individuals. During the study period there were 98,417 emergency department visits, 1,016 cases of self-harm, and 1,507 deaths from all causes. The top ten prescription patterns accounted for 69.3% of the data for individuals starting antidepressants at the fluoxetine equivalent of 20-39 mg. Additionally, we found associations between outcomes and dosage change. CONCLUSIONS: For 252,179 Veterans who served in Iraq and Afghanistan with subsequent MDD noted in their electronic medical records, we documented and described the major pharmacotherapy prescription patterns implemented by Veterans Health Administration providers. Ten patterns accounted for almost 70% of the data. Associations between antidepressant usage and outcomes in observational data may be confounded. The low numbers of adverse events, especially those associated with all-cause mortality, make our calculations imprecise. Furthermore, our outcomes are also indications for both disease and treatment. Despite these limitations, we demonstrate the usefulness of our framework in providing operational insight into clinical practice, and our results underscore the need for increased monitoring during critical points of treatment.

Utilizing Pharmacogenomics Results to Guide Antidepressant Selection: A Case Report.

The case discussion demonstrates the benefit of using Pharmacogenomic (PGx) results to aid in the selection of antidepressant therapy and improve response to treatment. Nearly half of patients diagnosed with major depressive disorder fail initial therapy and may require multiple trials of antidepressants. Genetic variation in several metabolic enzymes contribute to the variable response to antidepressant therapy. PGx testing provides an opportunity to inform antidepressant selection and optimize therapeutic outcomes, while minimizing risk of adverse events. A 79-year-old female who had been experiencing a suboptimal response to escitalopram following dose escalation over a period of three years was referred for a PGx consultation. A clinical pharmacist assessed significant drug-gene, drug-drug, and drug-drug-gene interactions, and relevant clinical information to recommend alternative antidepressant therapy, which resulted in mood improvement.

Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin.

BACKGROUND: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period. METHODS: Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466). FINDINGS: Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge's g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline. CONCLUSIONS: PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity. FUNDING: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.

Treatment-resistant depression patients with baseline suicidal ideation required more treatments to achieve therapeutic response with ketamine/esketamine.

BACKGROUND: There is an urgent need to identify interventions to reduce suicidality. We investigated the antisuicidal effects of intravenous (IV) ketamine and intranasal (IN) esketamine among patients with treatment-resistant depression (TRD) in a historical cohort study. METHODS: The Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) question 12 was used to measure suicidal ideation (SI). Cox proportional hazards models were used to evaluate associations between the number of treatments to response and baseline SI (yes, Q12 > 0 versus no, Q12 = 0), adjusting for covariates and modified baseline QIDS-SR score. We evaluated associations between the number of treatments to a 50 % reduction in SI score between IV and IN treatment. RESULTS: Fifty-two adults (62.5 % female, median age 49.1 years) received IV ketamine (71 %, n = 37) or IN esketamine (29 %, n = 15). Eighty-one percent of patients reported SI at baseline. Among those with baseline SI, 60 % had improved SI scores while 38 % did not change, and among those with no SI, 80 % did not change. After adjusting for covariates, the hazard ratios (HR) of response were significantly lower among those with baseline SI (HR = 0.36, 95 % CI, 0.14-0.92, p = 0.03). The number of treatments to achieve a 50 % reduction in SI score did not depend on group (IN esketamine vs. IV ketamine HR = 0.74 [95 % CI, 0.27-2.05]; p = 0.57). LIMITATIONS: Small sample size and lack of a placebo group. CONCLUSIONS: This study suggests that patients with baseline suicidal ideation require more treatments to achieve a response with ketamine or esketamine. The antisuicidal response seemed similar between IV ketamine and IN esketamine.

Trastorno por uso de cocaína y depresión: Cuando el diagnóstico clínico no es suficiente / Cocaine and depressive disorders: When standard clinical diagnosis is insufficient

Antecedentes: El consumo de cocaína es un creciente problema de saluden todo el mundo. Además, los pacientes con trastorno por consumode cocaína (TCC) presentan una alta comorbilidad con el trastornodepresivo mayor (TDM). Estos pacientes pueden presentar dos tipos deTDM: trastorno depresivo mayor primario (TDM-P) y trastorno depresivo mayor inducido por cocaína (TDM-IC). El objetivo de este estudio esevaluar las diferencias en la sintomatología depresiva (TDM-P vs. TDMIC) en los pacientes con TCC para mejorar su tratamiento. Métodos: Sellevó a cabo un análisis secundario en una muestra transversal de 160pacientes que presentaban TCC y algún TDM. La evaluación clínica,así como el diagnóstico diferencial entre TDM-P y TDM-IC, se realizóutilizando la entrevista PRISM. Resultados: Los hombres representaronel 80% de la muestra con una edad media de 38,61 años y el 64,5%sólo tenía estudios primarios. El diagnóstico de TDM-IC (61,3%) fuemás frecuente que el de TDM-P (38,7%). Los pacientes con TDM-ICmostraron una edad de aparición más temprana para el TCC. El 79,4%de los pacientes cumplían criterios para otro trastorno por consumo desustancias. Únicamente el criterio “Cambios en el peso o en el apetito” fueestadísticamente más prevalente (57,1%) en los pacientes con TDM-P.Conclusiones: Existen diferencias en el criterio “Cambios en el peso o en elapetito” entre TDM-P y TDM-IC. Se necesita más investigación a fin deobtener un diagnóstico diferencial entre los dos tipos de depresión yproporcionar un mejor tratamiento para los pacientes con TCC. (AU)

Background: Cocaine use is a growing global health problem and patients with cocaine use disorders (CUD) present several complications, including high rates of major depression. These subjects present two types of major depressive disorder (MDD): primary majordepressive disorder (P-MDD) and cocaine-induced major depressivedisorder (CI-MDD). To improve treatment, it is necessary to distinguish between both types. The aim of this study was to assess the differences in depressive symptomatology criteria (P-MDD vs CI-MDD)in CUD patients. Methods: Secondary data analysis was carried out witha cross-sectional sample of 160 patients presenting CUD and MDD.Clinical assessment was performed using the Psychiatric ResearchInterview for Substance and Mental Disorders (PRISM). A differential diagnosis was obtained between P-MDD and CI-MDD. Results: Menrepresented 80% of the sample, the mean age was 38.61 years, and64.5% had elementary studies. CI-MDD diagnosis (61.3%) was morefrequent than P-MDD (38.7%). There was a younger age of CUD onset in CI-MDD patients. In addition, 79.4% of the patients had anothersubstance use disorder diagnosis. The criterion “Changes in weight orappetite” was more prevalent (57.1%) in P-MDD group. Conclusions:We found differences in the criterion “Changes in weight or appetite”.Further research is needed in this field to establish a differential diagnosis and thus provide better treatment for CUD patients. (AU)

Predice la mejoría precoz inducida por los antidepresivos la respuesta/remisión? Análisis de los datos de un estudio naturalista en una muestra a gran escala de pacientes hospitalizados con depresión mayor / Does early improvement triggered by antidepressants predict response/remission? - Analysis of data from a naturalistic study on a large sample of inpatients with major depression

El inicio lento de acción de los antidepresivos y la elevada proporción de pacientes con una respuesta insuficiente, o no respondedores, son retos clínicos bien conocidos. Por esta razón, parece necesario identificar las variables predictoras de la respuesta e incluso, lo que es más importante, de la remisión. Se ha sugerido que la reducción de los síntomas depresivos en un estadio precoz del tratamiento antidepresivo podría predecir su resultado. El objetivo del presente estudio fue examinar si en un estudio naturalista a mayor escala, efectuado en una cohorte de pacientes hospitalizados con depresión mayor, se confirmaría esta hipótesis derivada de los ensayos aleatorizados y controlados (EAC), efectuados en pacientes ambulatorios. Los pacientes fueron tratados con diversos antidepresivos y medicación concomitante de acuerdo con el protocolo desarrollado a partir de las directrices clínicas basadas en la evidencia. Métodos La presente investigación fue un estudio naturalista prospectivo, a gran escala. Todos los pacientes (n=795) fueron hospitalizados y cumplían los criterios DSM-IV de depresión mayor de acuerdo con la structured clinical interview (SCID, ‘entrevista clínica estructurada’). Las evaluaciones se efectuaron cada 2 semanas. En dos visitas diferentes se examinaron diversas definiciones de mejoría precoz (reducción del 20, 25 y 30% en las puntuaciones totales basales obtenidas en la escala de depresión de Hamilton [HAMD-21]). Para las diferentes definiciones de mejoría precoz se calcularon la sensibilidad, especificidad y los valores predictivos. Se efectuaron análisis ROC (curva de eficacia diagnóstica), al igual que modelos de regresión logística. La respuesta se definió como una mejoría del 50% de la puntuación basal total obtenida en la escala HAMD-21 y la remisión como una puntuación ≤7 en el momento del alta. Además, se analizó el tiempo transcurrido hasta la respuesta calculando las estimaciones de supervivencia de Kaplan-Meier para la definición de la mejoría precoz «óptima» en comparación con ninguna. Se efectuaron análisis de subgrupo para examinar si los resultados eran homogéneos a través de los subgrupos de tratamiento. Resultados: El 48,8% de pacientes de la muestra del presente estudio manifestó remisión. La tasa de respuesta global fue del 79,6%. Una disminución del 20% en la puntuación basal total obtenida en la escala HAMD-21 en el día 14 proporcionó una sensibilidad del 75% y una especificidad del 59% para la predicción de la respuesta. Esta definición de mejoría precoz fue una variable predictora incluso más sensible de remisión (80%), con una especificidad limitada (43%). Un valor de la AUC de alrededor de 0,68 de la respuesta precoz (mejoría del 20%) indica una «predictividad» satisfactoria para ambos intervalos de tiempo examinados (día 14 y 28) y solo cambió ligeramente con los porcentajes más altos en la reducción de la puntuación (AUC=0,71 y 0,73, respectivamente). Más de un tercio (37%) de todos los pacientes que no habían mostrado mejoría en el día 14 seguían sin manifestarla en el curso tardío del tratamiento (casi la mitad de todos los pacientes [43%] en el día 28). Se obtuvieron resultados similares mediante los análisis de supervivencia de Kaplan-Meier. La prueba del log-rank reveló un tiempo significativamente más prolongado hasta la respuesta en pacientes sin mejoría precoz (p<0,0001). Limitaciones: Los resultados se evaluaron mediante un análisis post-hoc basado en datos obtenidos prospectivamente. Es preciso mencionar diversos problemas del diseño naturalista, en especial la ausencia de un grupo de control y que tan solo pudo considerarse un número limitado de factores de estratificación. Conclusión: Los resultados respaldan los hallazgos previos de que la mejoría precoz en las 2 primeras semanas puede predecir con una elevada sensibilidad la respuesta y la remisión posterior, incluso en pacientes hospitalizados que presentan una depresión más grave. Puesto que empleamos un diseño de estudio naturalista, los datos pueden considerarse la replicación de los resultados previos extraídos de los EAC en un contexto naturalista. Encontramos un efecto antidepresivo global que fue constante a través de los subgrupos de tratamiento con respecto a los valores de sensibilidad. No obstante, somos conscientes de la imposibilidad de los estudios sobre efectividad para extraer relaciones causales del tratamiento a partir de una estrategia no controlada. Sin embargo, es posible que la replicación de los estudios previos indique que durante el tratamiento, en caso de ausencia de mejoría precoz, puede acelerarse un cambio de fármaco (AU)

Background: Delayed onset of efficacy of antidepressants and a high proportion of depressed patients being poor or non-responders to antidepressants are well known clinical challenges. Therefore, it seems to be necessary to identify predictors for response and –even more important – for remission. It has been suggested that reduction of depressive symptoms at an early stage of antidepressant treatment may predict treatment outcome. Our objective was to test, if this hypothesis derived from randomized controlled studies (RCTs) in outpatients, would be confirmed in a large naturalistic study in a cohort of inpatients with major depression. Patients were treated with various antidepressants and co-medication according to the protocol based on evidence based clinical guidelines. Methods: This was a large naturalistic prospective study. All patients (N=795) were hospitalized and met DSM-IV criteria for major depression according to a structured clinical interview (SCID). Assessments were conducted biweekly. Several definitions of early improvement (20%, 25% and 30% reduction in HAMD-21 baseline total scores) at two different visits were tested. Sensitivity, specificity and predictive values were calculated for the different definitions of early improvement. ROC-analyses as score and remission as a score of ≤7 at discharge. Additionally, time to response was analyzed by computing Kaplan–Meier survival estimates for the "best" early improvement definition in comparison to non early improvement. Subgroup analyses were conducted to test whether the results were consistent across treatment subgroups. Results: In total, 48.8% of patients in our sample were remitters. The overall response rate was 79.6%. A 20% reduction of HAMD-21 total baseline score at Day 14 provided a sensitivity of 75% and a specificity of 59% for response prediction. This definition of early improvement was an even more sensitive predictor for remission (80%) with a limited specificity (43%). The AUC value of about 0.68 for early response (20% improvement) indicates good predictability for both time intervals tested (Day 14 and Day 28) and changed only marginally with increased percentages in score reduction (AUC=0.71 and 0.73, respectively). More than one third (37%) of all patients who had not improved at Day 14 showed not response in the later treatment course (this was the case for nearly half of all patients (43%) at Day 28). Similar results were obtained by Kaplan–Meier survival analyses. Log-rank test showed significantly longer time to response in patients with non-early improvement (pb0.0001). Limitations: Results were assessed by a post-hoc analysis based on prospectively collected data. Several caveats of a naturalistic design must be mentioned, especially there was no control group and only a limited number of stratification factors could be considered. Conclusion: The results support earlier findings that early improvement in the first two weeks may predict with high sensitivity later response and remission, even in hospitalized patients suffering from a more severe degree of depression. Since we used a naturalistic study design, the data may be considered as a replication of previous results drawn from RCTs in a naturalistic environment. We found a global antidepressant effect which was consistent across treatment subgroups regarding sensitivity values. However, we are aware of the inability of effectiveness studies to draw causal treatment relationships from the uncontrolled approach. Nevertheless, the replication of previous results might indicate that a drug switch during treatment in case of lack of early improvement could be accelerated (AU)